Searching for new therapeutic options for the uncommon pathogen Mycobacterium chimaera: an open drug discovery approach

Cantillon, Daire; Goff, Aaron; Taylor, Stuart A.; Salehi, Emad; Fidler, Katy; Stoneham, Sarah J.; Waddell, Simon J.

doi:10.1016/s2666-5247(21)00326-8

Cited by 16 publications

(11 citation statements)

References 25 publications

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“…Highly polar drugs such as fosmidomycin have previously been associated with poor efficacy against T. gondii due to a lack of parasite plasma membrane permeability (Nair et al 2012; Baumeister et al 2011). MMV675968 is a dually active T. gondii compound and has been shown to be a potent inhibitor of the dihydrofolate reductase (DHFR) in a range of pathogens (Songsungthong et al 2019, 2021; Kim et al 2021; Borba-Santos, Vila, and Rozental 2020; Nugraha et al 2019; Rollin-Pinheiro et al 2021; Vila and Lopez-Ribot 2017; Cantillon et al 2022). Although its target in T. gondii remains to be identified, pyrimethamine, which inhibits the dihydrofolate reductase-thymidylate synthetase in T. gondii is inactive against both in vitro and brain-resident bradyzoites (Christiansen et al 2022; Montazeri et al 2018).…”

Section: Discussionmentioning

confidence: 99%

Screening the MMV Pathogen Box reveals the mitochondrialbc₁-complex as a drug target in matureToxoplasma gondiibradyzoites

Maus,

Putrianti,

Hoffmann

et al. 2023

Preprint

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The apicomplexan parasiteToxoplasma gondiiinfects 25-30% of the global human population and can cause life-threatening diseases in immunocompromised patients. The chronic infectious form of the parasite, bradyzoites, persist within cysts in brain and muscle tissues and are responsible for its transmission and remission. Currently available treatment options are very limited and include antimicrobials currently in development novel developmental treatments. They are only effective against the fast replicating tachyzoites but fail to eradicate the chronic stages ofT. gondii. The cause of these treatment failures remains unclear. We utilized the recently developed human myotube-based culture model to screen compounds from the MMV Pathogen Box against pan-drug tolerantin vitrobradyzoites. We identified various hit compounds that show simultaneous activity against tachyzoites and bradyzoites. Stable isotope-resolved metabolic profiling identified the mitochondrial bc1-complex as a target of bradyzocidal compounds. Comparing the impact of bradyzocidal with non-bradyzocidal coenzyme Q analogs on parasite ATP levels suggests active and essential mitochondrial ATP production in mature bradyzoites.

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Section: Discussionmentioning

confidence: 99%

Screening the MMV Pathogen Box reveals the mitochondrialbc₁-complex as a drug target in matureToxoplasma gondiibradyzoites

Maus,

Putrianti,

Hoffmann

et al. 2023

Preprint

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“…Fewer new cardiovascular drugs are successful through clinical trials, mainly due to the lack of clarity about drug toxicity and potential drug effects. Thus, the demand for drug toxicity assessment and new drugs for heart disease is still steadily increasing [ 135 , 136 , 137 ].…”

Section: Screening Drugs and Toxicity Detection Of Ipsc-derived Organ...mentioning

confidence: 99%

Application Prospect of Induced Pluripotent Stem Cells in Organoids and Cell Therapy

Zhang,

Qian,

Song

et al. 2024

IJMS

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Since its inception, induced pluripotent stem cell (iPSC) technology has been hailed as a powerful tool for comprehending disease etiology and advancing drug screening across various domains. While earlier iPSC-based disease modeling and drug assessment primarily operated at the cellular level, recent years have witnessed a significant shift towards organoid-based investigations. Organoids derived from iPSCs offer distinct advantages, particularly in enabling the observation of disease progression and drug metabolism in an in vivo-like environment, surpassing the capabilities of iPSC-derived cells. Furthermore, iPSC-based cell therapy has emerged as a focal point of clinical interest. In this review, we provide an extensive overview of non-integrative reprogramming methods that have evolved since the inception of iPSC technology. We also deliver a comprehensive examination of iPSC-derived organoids, spanning the realms of the nervous system, cardiovascular system, and oncology, as well as systematically elucidate recent advancements in iPSC-related cell therapies.

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“…According to the in vitro antimicrobial drug susceptibility testing, A study ( Cantillon et al, 2022 ) using an open drug discovery approach found that oxazolidinones such as linezolid and doxycycline have excellent tissue penetration properties and are actively potent against M. chimaera . Two case reports ( Shimizu et al, 2012 ; Wang C. J. et al, 2022 ) recommend combined therapy with adequate debridement and sensitive antibiotic administration for soft tissues in patients infected with M. smegmatis .…”

Section: Main Textmentioning

confidence: 99%

Treatment of non-tuberculosis mycobacteria skin infections

Wang,

Jia,

2023

Front. Pharmacol.

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Non-tuberculosis mycobacteria (NTM) skin infections have become increasingly prevalent in recent years, presenting a unique challenge in clinical management. This review explored the complexities of NTM infections localized to the superficial tissues and provided valuable insights into the optimal therapeutic strategies. The antibiotic selection should base on NTM species and their susceptibility profiles. It is recommended to adopt a comprehensive approach that considers the unique characteristics of superficial tissues to improve treatment effectiveness and reduce the incidence of adverse reactions, infection recurrence, and treatment failure. Infection control measures, patient education, and close monitoring should complement the treatment strategies to achieve favorable outcomes in managing NTM skin infections. Further efforts are warranted to elucidate factors and mechanisms contributing to treatment resistance and relapse. Future research should focus on exploring novel treatment options, innovative drug development/delivery platforms, and precise methodologies for determining therapeutic duration. Longitudinal studies are also needed to assess the long-term safety profiles of the integrated approaches.

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Searching for new therapeutic options for the uncommon pathogen Mycobacterium chimaera: an open drug discovery approach

Cited by 16 publications

References 25 publications

Screening the MMV Pathogen Box reveals the mitochondrialbc₁-complex as a drug target in matureToxoplasma gondiibradyzoites

Screening the MMV Pathogen Box reveals the mitochondrialbc₁-complex as a drug target in matureToxoplasma gondiibradyzoites

Application Prospect of Induced Pluripotent Stem Cells in Organoids and Cell Therapy

Treatment of non-tuberculosis mycobacteria skin infections

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Searching for new therapeutic options for the uncommon pathogen Mycobacterium chimaera: an open drug discovery approach

Cited by 16 publications

References 25 publications

Screening the MMV Pathogen Box reveals the mitochondrialbc1-complex as a drug target in matureToxoplasma gondiibradyzoites

Screening the MMV Pathogen Box reveals the mitochondrialbc1-complex as a drug target in matureToxoplasma gondiibradyzoites

Application Prospect of Induced Pluripotent Stem Cells in Organoids and Cell Therapy

Treatment of non-tuberculosis mycobacteria skin infections

Contact Info

Product

Resources

About

Screening the MMV Pathogen Box reveals the mitochondrialbc₁-complex as a drug target in matureToxoplasma gondiibradyzoites

Screening the MMV Pathogen Box reveals the mitochondrialbc₁-complex as a drug target in matureToxoplasma gondiibradyzoites